The goal of this project is to understand neuroimmune mechanisms of depression in adults with HIV infection through analysis of plasma and CSF exosomes and the relationship of exosome protein cargo to inflammation and tryptophan-kynurenine metabolism. Systemic inflammation in HIV infection and other conditions is associated with increased risk of depression through mechanisms involving altered tryptophan-kynurenine metabolism and other unknown mechanisms. Exosomes mediate cell-cell communication during inflammation and other conditions, but their role in neuroimmune interactions involved in depression have not been defined. Preliminary studies showed increased levels of circulating exosomes in HIV patients on ART compared to controls. Moreover, we identified heat shock proteins, Wnt proteins, and other protein cargo in these exosomes that correlate with HIV status, altered tryptophan-kynurenine metabolism, and depressive symptoms. Given that dysregulated Wnt/GSK3-? signaling and inflammatory responses have been linked to depression and other mood disorders, these findings suggest that circulating exosomes may play a role in neuroimmune interactions that impact depression through effects on Wnt/GSK3-? and/or TLR-mediated signaling. To address these questions, we will use clinical samples and data from well characterized HIV+ cohorts followed longitudinally to characterize plasma and CSF exosomes and their relationship to depression, inflammation markers, and tryptophan-kynurenine metabolites. Bioinformatics, computational modeling, and cell culture models will be used to build and test models that predict depression status and relevant pathways. This approach may define novel relationships between circulating exosome cargo and neuroimmune mechanisms of depression in HIV infection, potentially suggesting new therapeutic targets based on the biology of exosomes.